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• W2082034240 abstract "Transforming growth factor β (TGF-β) has a dual role in carcinogenesis, acting as a growth inhibitor in early tumor stages and a promoter of cell proliferation in advanced diseases. Although this cellular phenomenon is well established, the underlying molecular mechanisms remain elusive. Here, we report that sequential induction of NFAT and c-Myc transcription factors is sufficient and required for the TGF-β switch from a cell cycle inhibitor to a growth promoter pathway in cancer cells. Mechanistically, TGF-β induces in a calcineurin-dependent manner the expression and activation of NFAT factors, which then translocate into the nucleus to promote c-Myc expression. In response to TGF-β, activated NFAT factors bind to and displace Smad3 repressor complexes from the previously identified TGF-β inhibitory element (TIE) to transactivate the c-Myc promoter. c-Myc in turn stimulates cell cycle progression and growth through up-regulation of D-type cyclins. Most importantly, NFAT knockdown not only prevents c-Myc activation and cell proliferation, but also partially restores TGF-β-induced cell cycle arrest and growth suppression. Taken together, this study provides the first evidence for a Smad-independent master regulatory pathway in TGF-β-promoted cell growth that is defined by sequential transcriptional activation of NFAT and c-Myc factors. Transforming growth factor β (TGF-β) has a dual role in carcinogenesis, acting as a growth inhibitor in early tumor stages and a promoter of cell proliferation in advanced diseases. Although this cellular phenomenon is well established, the underlying molecular mechanisms remain elusive. Here, we report that sequential induction of NFAT and c-Myc transcription factors is sufficient and required for the TGF-β switch from a cell cycle inhibitor to a growth promoter pathway in cancer cells. Mechanistically, TGF-β induces in a calcineurin-dependent manner the expression and activation of NFAT factors, which then translocate into the nucleus to promote c-Myc expression. In response to TGF-β, activated NFAT factors bind to and displace Smad3 repressor complexes from the previously identified TGF-β inhibitory element (TIE) to transactivate the c-Myc promoter. c-Myc in turn stimulates cell cycle progression and growth through up-regulation of D-type cyclins. Most importantly, NFAT knockdown not only prevents c-Myc activation and cell proliferation, but also partially restores TGF-β-induced cell cycle arrest and growth suppression. Taken together, this study provides the first evidence for a Smad-independent master regulatory pathway in TGF-β-promoted cell growth that is defined by sequential transcriptional activation of NFAT and c-Myc factors." @default.
• W2082034240 created "2016-06-24" @default.
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• W2082034240 date "2010-08-01" @default.
• W2082034240 modified "2023-10-18" @default.
• W2082034240 title "Sequential Activation of NFAT and c-Myc Transcription Factors Mediates the TGF-β Switch from a Suppressor to a Promoter of Cancer Cell Proliferation" @default.
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• W2082034240 doi "https://doi.org/10.1074/jbc.m110.100438" @default.
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